DChiroInositol and its Role in Insulin Action

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Slide 1 :

Allomed Pharmaceuticals D-Chiro-Inositol and its Role in Insulin Action and Insulin Resistance J. Larner, M.D.,Ph.D.

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The Search for an Insulin Mediator (1977- present) Development of Two Enzyme Bioassays Isolation of Inositol Glycans Isolated from Rat Liver Scale up to Beef Liver Structural Determination of Pinitol Galactosamine Pseudodisaccharide Mn2+ Chelate Bioactivity of Synthetic Pseudodisaccharide (INS-2) Allosteric Mechanism of Action of INS-2 activation of PP2C Pathophysiology of Inositol Imbalance and Relation to Insulin Resistance Epimerase Conversion of Myo-Inositol to Chiro-Inositol Studies on Epimerization Defects in Diabetes Treatment Strategies Preclinical Studies (Rats, Primates) Clinical Trials (Phase I and II) Antioxidant Effects Future Therapeutic Agents Conclusions

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The existence of a putative mediator of insulin action was first proposed by Larner and associates on the basis of dissociation of several actions of insulin, which suggested that a second step after insulin binding must involve divergent pathways. For example, during rat heart perfusion, insulin stimulated glucose transport but did not activate glycogen synthase (GS) activity. Furthermore, during treatment of rat diaphragm with the sulfhydryl-modifying reagent N-ethylmaleimide, insulin activated GS with no effect on glucose transport. These early observations, demonstrating that insulin signaling could proceed in one pathway while another pathway was blocked, argued against a unitary mechanism of action. Instead, they suggested the possibility of generation of a mediator (or mediators) with the requirement that it (they) impart specific directionality to the signaling pathways.

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Muscle Walkenbach, RJ. et al. Mol. & Cellular Biochem. 19, 31,1978 A. Inactivation of cAMP-dependent Protein Kinase by Insulin B. Inactivation of cAMP-dependent Protein Kinase by Insulin Liver

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Larner, J. (Huang, LC) et al. Ann. New York Academy of Science.573, 297, 1989 Denton, RM, et al. Ann. New York Academy of Science. 573, 285, 1989

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Separation of Inositol Glycans from Rat Liver pH 2.0 (HCl) pH 1.3 (HCl) Larner, J. et al. BBRC, 151, 1416, 1988

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Galactosamine standard Galactosamine standard pH 1.3 control pH 1.3 insulin pH 2.0 control pH 2.0 insulin Purification of Two Inositol Glycans from Rat Liver Larner, J. et al. Cold Spring Harbor Symp. LIII, 965, 1988

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Composition of pH 2.0 Insulin Mediator Inositol Glycan pH 2.0 Fraction HPLC ProteinPak 60 Purified 4 N TFA 4 hrs 100 6 N HCl 48 hrs 100 Galactosamine + Pinitol (3-O-methyl D-chiro-inositol) D-Chiro-inositol Molar ratio of D-Chiro-inositol Galactosamine = 1.2 1.0 Larner, J. et al. BBRC, 151, 1416, 1988

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INOSITOL ISOMERIC STRUCTURES myo-inositol L-chiro-inositol D-chiro-inositol 1 2 5 4 6 3

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Mn 2+ amino group of galactosamine hydroxyl group of pinitol INS2-Pinitol ß 1,4 Galactosamine methyl group of pinitol Larner, J. et al. J Med Chem. 46, 3283, 2003.

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Allomed Pharmaceuticals Synthetic INS-2 Shows Anomeric Specificity to Decrease Hyperglycemia in Diabetic STZ Rats ß-1,4 anomer a-1,4 anomer Larner, J. et al. J Med Chem. 46, 3283, 2003.

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Allomed Pharmaceuticals Synthetic INS-2 Shows a Dose Response Relationship to Decrease Hyperglycemia in Diabetic STZ Rats 20 mg/kg 8 mg/kg 2 mg/kg control Larner, J. et al. J Med Chem. 46, 3283, 2003.

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Allomed Pharmaceuticals INS-2 Sensitizes Insulin Action in Hepatoma Cells to Stimulate Glycogen Synthesis INS2 + 10 nM Insulin INS2 only Larner, J. et al. J Med Chem. 46, 3283, 2003.

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INS-2 Mimics Insulin Action to Stimulate Testosterone Synthesis in Human Thecal Ovarian Cells Nestler, JE et al. J Clin Endo. Metab. 83, 2001, 1998

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Allosteric and Catalytic Binding Sites for INS-2 and Substrate Peptide on Phosphatase PP2C Catalytic Allosteric Brautigan, et al. (Brown/Larner), Biochemistry, 44, 11067, 2005.

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Proposed Mechanism of Allosteric Actionof INS-2 on Phosphatase PP2C Brautigan, et al. (Brown/Larner), Biochemistry, 44, 11067, 2005.

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D163A Mutant Shows Loss of Allosteric Activation of with Full Retention of Catalytic Activity Brautigan, et al. (Brown/Larner), Biochemistry, 44, 11067, 2005.

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Pathophysiology of Inositol Imbalance and Its Relationship to Insulin Resistance

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Suzuki, S. et al. New Directions in Research and Clinical Works for Obesity and Diabetes Mellitus. Elsevier, 197, 1991. Inositol Imbalance in Type II Diabetic Rat Urine

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Inositol Imbalance in Human Type II Diabetic Urine

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Ratio of Myo-inositol to Chiro-inositol in Human Diabetic Urine is Markedly Increased Myo/Chiro Ratio in Human Urine Larner, J. and Craig JW. Diabetes Care, 19, 76, 1996.

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Decreased Insulin-like pH 2.0 Mediator Bioactivity in Human Type II Diabetic Tissues Asplin, I. et al. PNAS, 90, 1524, 1993 Hemodialysate Muscle Urine

Slide 25 :

Control Subjects Type II Diabetic Subjects Decreased Insulin-like pH 2.0 Mediator Bioactivity in Human Type II Diabetic Blood During Glucose Tolerance Test Shashkin, PN (Katz) et al. Diabetalogia, 40, 557, 1997 Time after glucose Ingestion (min) PDH activity (% of 0 min)

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Altered D-Chiro-Inositol Urinary Clearance in Women with Polycystic Ovary Syndrome Text Text Baillargeon et al. (Nestler) J Clin Endocrinol Metab 89:242-249 (2004)

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Scioscia, et al. (Rademacher) Journal of Clinical Endocrinology and Metabolism 91(2):711 (2006) Preeclampsia Patients Release Lower Amounts of Insulin Stimulated Inositol Glycan Mediator from Human Placental Membranes Preeclamptic Patients Control Patients

Slide 28 :

Type II Japanese Diabetics Excrete Lower Levels of Chiro-inositol Suzuki, S. et al. Diabetes Care, 17, 1465, 1994

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Urinary chiro-inositol (µmol/day) SI (X10-4 min-1 mU-1 ml-1) Decreased Urinary Chiro-Inositol Excretion Correlates with Decreased Insulin Sensitivity Suzuki, S. et al. Diabetes Care, 17, 1465, 1994

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Conversion of [3H] Myo-inositol to [3H] Chiro-inositol is Defective in GK Type II Diabetic Rats Liver Fat Muscle % Conversion Control Diabetic Pak Y. et al. Molecules and Cells, 8, 301, 1998

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Nucleotide Cofactor Requirements for Myo to Chiro-Inositol Epimerase Enzymatic Activity Indicate an Oxido-Reductive Mechanism Sun, T-h, et al. (Nadler) BBRC, 293, 1092, 2002

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Myo-inositol to Chiro-inositol Epimerase Activityis Decreased in GK Type II Diabetic Rat Tissues Normal Wistar GK Type II Diabetic Sun, T-h, et al.(Nadler). BBRC, 293, 1092, 2002

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Oral Administration of D-Chiro-inositol Restores Euglycemia in STZ Diabetic Rats Ortmeyer, HK, et al. Endocrinology, 132, 646, 1993

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Oral Administration of D-Chiro-inositol Improves Glycemic Control in Insulin Resistant Primates Control D-Chiro-inositol Ortmeyer, HK et al. Obesity Research, 3, 605S, 1995

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Oral Administration of D-Chiro-inositol Improves Ovulation in Women with Polycystic Ovary Syndrome D-Chiro-inositol Placebo Ovulated Did not ovulate Number of Subjects Nestler, JE et al. NEJM, 340, 1314, 1999

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Vasorelaxant response to acetylcholine in aortic rings of 4-week alloxan-diabetic rats treated with vehicle (saline) or D-chiro-inositol (20 mg/kg/12 h; p.o.). Data are mean ± SEM of 6 experiments. * p<0.05 (diabetic + D-chiro-inositol vs. diabetic + saline), # p<0.05 (normoglycemic vs. diabetic + D-chiro-inositol), ANOVA followed by Bonferroni. Oral Administration of D-Chiro-inositol Prevents Endothelial Dysfunction in Alloxan Diabetic Rat Aortic Rings Nascimento, NRF et al. PNAS, 103, 218, 2006

Slide 41 :

Vascular reactivity to acetylcholine of the arteriolar mesenteric bed of normoglycemic and 4-week alloxan-diabetic rats treated with vehicle (saline) or D-chiro-inositol (20 mg/kg/12 h; p.o.). Data are mean ± SEM of 6 experiments. * p<0.05, (diabetic + D-chiro-inositol vs. diabetic + saline), ANOVA, followed by Bonferroni. Oral Administration of D-Chiro-inositol Prevents Endothelial Dysfunction in Alloxan Diabetic Rat Mesenteric Bed Vessels Nascimento, NRF et al. PNAS, 103, 218, 2006

Slide 42 :

Endothelium-independent relaxation evoked by sodium nitroprusside (10-16 to 10-4 M) in aortic rings gathered from normoglycemic, 4-week alloxan-diabetic rats treated with saline or D-chiro-inositol (20 mg/kg/12h). The data are expressed as mean ± SEM of six experiments. * p<0.05, (diabetic + D-chiro-inositol vs. diabetic + saline), ANOVA followed by Bonferroni. Smooth Muscle is Normal and Endothelium is Defective in Diabetic Vasculature as Shown by Nitroprusside Administration to Rat Aortic Rings Nascimento, NRF et al. PNAS, 103, 218, 2006

Slide 43 :

Effect of dibutyryl D-Chiro-Inositol (db-DCI) in the vasorelaxant effect of the endothelium-dependent agonist acetylcholine in the renal vascular bed. The data are expressed as mean ± SEM of 8 experiments. * p<0.05 vs. responses obtained in tissues from diabetic rabbits and * p<0.05 vs. responses obtained in tissues from euglycemic rabbits. Acute Administration of D-Chiro-inositol Analog Reverses Endothelial Dysfunction in Alloxan Diabetic Rabbit Kidney Nascimento, NRF et al. PNAS, 103, 218, 2006 Diabetic + dibutyryl D-Chiro-Inositol Euglycemic + vehicle Diabetic + vehicle

Slide 44 :

D-Chiro-inositol and D-Chiro-inositol Analog Depress Elevated ROS in Bovine Endothelial Cells Incubated in High Glucose Nascimento, NRF (Brownlee) et al. PNAS, 103, 218, 2006

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D-Chiro-inositol Analog Prevents Three Sequelae of Elevated ROS in Bovine Endothelial Cells C B A 30 mM Glucose + dibutyryl D-Chiro-inositol Nascimento, NRF (Brownlee) et al. PNAS, 103, 218, 2006

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Inositols Reduce ROS Generated in a Xanthine/Xanthine Oxidase System Nascimento, NRF et al. PNAS, 103, 218, 2006

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Mechanism of Inositol Action to Reduce Elevated ROS In a Xanthine/Xanthine Oxidase System Requires Fe+3 Nascimento, NRF et al. PNAS, 103, 218, 2006

Slide 48 :

Unknown Chiro-inositol Glycans Isolated From Beef Liver Have Enhanced Activity Over INS2 B, C and D = three unknown chiro-inositol glycans

Slide 49 :

The combination of metabolic, i.e. insulin-mimetic, and antioxidant properties of D-chiro-inositol and its derivatives in the face of an inositol imbalance associated with insulin resistance is worthy of further investigation. It opens unique avenues for therapy and constantly drives me to further understand the basic mechanisms. Conclusions J Larner

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